Imaging-Guided Percutaneous Endovascular Biopsy Applied in Patients with Pulmonary Artery Masses: A Review.

INTRODUCTION: Pulmonary artery (PA) masses are rare. Distinguishing PA tumours from embolism is sometimes difficult, and surgical biopsy is expensive and risky. We aimed to evaluate the efficacy of imaging-guided percutaneous endovascular biopsy (PEB) for obtaining tissues for histological diagnosis. METHODS: We searched Cochrane, Medline, Embase, and Web of Science for PEB trials involving patients with PA masses, published from the inception of the database until August 2023. RESULTS: We retrospectively reviewed 33 studies including 87 patients (median age 55 ± 69.3 years, 44 men) with PA masses who underwent a total of 110 PEBs. Of these patients, 34.5% (n = 38) underwent PEB-catheter aspiration (PEB-CA), 50.9% (n = 56) underwent PEB-forceps biopsy (PEB-FB) and 2.7% (n = 3) underwent PEB-directional atherectomy (PEB-DA). The most common histological aetiology of PA masses was mesenchymal tumours (n = 67, 75.9%). Tumour embolism (n = 6, 6.9%) and pulmonary embolism (n = 3, 3.4%) were the second and third most common types of PA masses, respectively. The technical success rates of PEB-CA, PEB-FB and PEB-DA were 92.1%, 94.6% and 100% (p = 0.796), respectively. Histopathological analysis provided clinical diagnostic success rates of 44.7%, 85.7% and 100% for PEB-CA, PEB-FB and PEB-DA (p < 0.001), respectively. In pairwise comparison, PEB-FB had a higher success rate in pathological diagnosis than PEB-CA (p = 0.000). Apart from one patient suffering from haemorrhagic cardiac tamponade, no other complications occurred. CONCLUSION: Imaging-guided PEB is a safe and effective technique for the early pathological diagnosis of PA masses.

International trends in pulmonary hypertension mortality between 2001 and 2019: Retrospective analysis of the WHO mortality database.

Background: There are limited published data on mortality trends in pulmonary hypertension (PH) worldwide. The objective of this study was to assess the PH-related mortality and time trends in the general population over the past 20 years. Material and methods: We used country-level PH mortality data from the World Health Organization (WHO) mortality database (2000-19), using the International Classification of Diseases, tenth revision (ICD-10) codes (I27.0, I27.2, I27.8, or I27.9). The average annual percentage changes (AAPCs) were calculated to describe mortality trends. Results: Fifty-four countries were included in this study. Between 2017 and 2019, the average age-standardized death rates (per 100,000) were 0.80 and 0.87 for males and females, respectively. Joinpoint analyses revealed a decreasing PH mortality trend for the overall population from 2000 to 2019 (AAPC -3.2 [95% confidence interval (CI) -4.1 to -2.4]), which was consistent between males and females (males: AAPC -5.3 [95% CI -6.2 to -4.4], females: AAPC -1.7 [95% CI -2.4 to -0.9]). When the estimates were stratified by etiology, we found that the mortality rates from idiopathic pulmonary arterial hypertension (I27.0) and pulmonary heart disease (unspecified, I27.9) had decreased significantly, while the mortality rates in other secondary PH (I27.2) and other specified pulmonary heart diseases (I27.8) had significantly increased. In addition, there were substantial differences in mortality rates and time trends across countries. Conclusion: Although an overall decrease in PH mortality trends over the past two decades, there were substantial differences across countries. For countries with high or rising mortality rates, more efforts are needed to reduce the mortality.

Diabetic endothelial microangiopathy and pulmonary dysfunction.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Preclinical Characterization of XL092, a Novel Receptor Tyrosine Kinase Inhibitor of MET, VEGFR2, AXL, and MER.

The multi-receptor tyrosine kinase inhibitor XL092 has been developed to inhibit the activity of oncogenic targets, including MET, VEGFR2, and the TAM family of kinases TYRO3, AXL and MER. Presented here is a preclinical evaluation of XL092. XL092 causes a significant decrease in tumor MET and AXL phosphorylation (P < 0.01) in murine Hs 746T xenograft models relative to vehicle, and a 96% inhibition of VEGFR2 phosphorylation in murine lungs. Dose-dependent tumor growth inhibition with XL092 was observed in various murine xenograft models, with dose-dependent tumor regression seen in the NCI-H441 model. Tumor growth inhibition was enhanced with the combination of XL092 with anti-PD-1, anti-programmed death ligand-1 (PD-L1), or anti-CTLA-4 compared with any of these agents alone in the MC38 murine syngeneic model and with anti-PD-1 in the CT26 colorectal cancer survival model. In vivo, XL092 promoted a decrease in the tumor microvasculature and significant increases of peripheral CD4+ T cells and B cells and decreases in myeloid cells versus vehicle. Significant increases in CD8+ T cells were also observed with XL092 plus anti-PD-1 or anti-PD-L1 versus vehicle. In addition, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.

MiR-124-3p targeting PDE4B attenuates LPS-induced ALI through the TLR4/NF-κB signaling pathway.

BACKGROUND: A large number of studies have found that microRNAs (miRNAs) and phosphodiesterase 4 (PDE4) are crucial regulators of inflammatory responses in acute lung injury (ALI). OBJECTIVE: This study will explore the protective effect of miR-124-3p on ALI and its related mechanism. METHODS: The ALI mouse model was established by intratracheal administration of lipopolysaccharide (LPS) and evaluated by haematoxylin and eosin (HE) staining, lung injury score, inflammation factors, polymorphonuclear leukocyte (PMN) count, total protein and lung wet weight/dry weight (W/D) ratio. MiR-124-3p was overexpressed in vivo by intratracheal administration of miR-agomir, and PDE4B was expressed at low level in vivo by intratracheal administration of a PDE4B inhibitor. The mRNA expression level was detected by qRT-PCR, and the protein expression level was detected by Western blot. The relationship between miR-124-3p and PDE4B was detected by dual-luciferase activity assay. RESULTS: We found that miR-124-3p was downregulated in LPS-induced ALI. Overexpression of miR-124-3p alleviated lung injury by inhibiting the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, we confirmed that miR-124-3p suppressed the TLR4/NF-κB signaling pathway by directly targeting PDE4B. CONCLUSION: miR-124-3p targeting PDE4B had a protective effect on LPS-induced ALI by inhibiting the TLR4/NF-κB signaling pathway.

Clinical characteristics and postoperative outcomes of systemic artery-to-pulmonary vessel fistula in hemoptysis patients.

OBJECTIVES: To investigate the clinical characteristics and outcomes on the success of bronchial arterial embolization (BAE) in patients with and without systemic artery-to-pulmonary vessel fistula (SA-PF) and to evaluate the feasibility of CTA in the assessment of SA-PF. METHODS: We retrospectively enrolled 420 consecutive patients that underwent BAE for hemoptysis control in our hospital from September 2011 to May 2019. The clinical characteristics, preprocedural CTA findings, BAE procedural findings, and follow-up outcomes were collected. Patients were divided into two groups according to DSA findings: patients with SA-PF and those without. RESULTS: A total of 184 (43.7%) patients presented with SA-PF. Pneumonia was less likely to be the concomitant condition in patients with SA-PF (p < 0.001). The mean number of culprit arteries per patient was significantly higher in patients with SA-PF compared to that in patients without SA-PF (p = 0.017). The SA-PF patients saw a greater probability of recurrence (HR: 2.782, 95% CI: 1.617-4.784, p < 0.001). SA-pulmonary venous fistula (SA-PVF) favored lower hemoptysis recurrence rate (HR: 0.199, 95%CI: 0.052-0.765, p = 0.019). SA-pulmonary artery fistula (SA-PAF) can be detected by optimized CTA protocol with a detection rate of 65.3% (49/75). CONCLUSIONS: The presence of SA-PF is an independent risk factor predicting early recurrence of hemoptysis after BAE. SA-PVF seems to be a protective factor for longer hemoptysis control compared to SA-PAF. Optimized preprocedural CTA is a reliable examination to identify SA-PAF. KEY POINTS: • The appearance of SA-PF is associated with a greater probability of early recurrent hemoptysis after bronchial artery embolization. • The presence of SA-PVF seems to be a protective factor for longer hemoptysis control after BAE compared to SA-PAF. • Optimized CTA protocol seems to be a promising auxiliary examination to detect SA-PAF.

CT-guided transthoracic pulmonary artery catheterization: an experimental study in a porcine model.

OBJECTIVES: We investigated the safety and feasibility of CT-guided transthoracic pulmonary artery catheterization (TPAC) in a porcine model. METHODS: Procedures were conducted on ten mature Bama miniature pigs. After anesthesia, chest CT was performed in the left lateral decubitus position to determine the puncture route. Under the guidance of multiple CT scans, the introducer sheath was inserted from the right chest wall of the pig into the right pulmonary artery using the Seldinger technique. Then, a catheter connected with a transducer was inserted into the sheath to measure the pulmonary artery pressure. Finally, an active approximator was used to close the puncture site on the pulmonary artery. The pigs were followed up for 8 weeks to evaluate the operation-related complications and survival. RESULTS: Ten of 11 CT-guided TPAC procedures were successfully performed on ten pigs, rendering a technical success rate of 90.9%. One pig had hemoptysis while the needle was being inserted during the first operation, and a second procedure was successfully conducted 17 days later. Other complications, including pulmonary bleeding along the needle track (3 of 11; 27.3%), unclosed pulmonary artery puncture sites (3 of 10; 30%), pneumothorax (1 of 11; 9.1%), and hemopericardium (1 of 11; 9.1%), spontaneously resolved without complication-specific treatment. The mean pulmonary arterial pressure was 32 ± 17.6 mmHg. All animals survived the procedure and reached the end of the follow-up period. CONCLUSIONS: CT-guided TPAC is feasible and safe in a porcine model, serving as a potential alternative pathway for pulmonary artery intervention. KEY POINTS: • TPAC is feasible and safe in a porcine model, serving as a potential alternative pathway for pulmonary artery intervention. • This novel approach allows for faster access to the pulmonary artery, and it might be easier to operate the tip of the catheter to super-select the intent branch of the pulmonary artery. • TPAC can be an alternative pulmonary artery intervention pathway in patients with mechanical right-heart valves, great-vessel transposition, and other obstacles.

Bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB) for intubated patients with severe lung diseases.

BACKGROUND: Examinations based on lung tissue specimen can play a significant role in the diagnosis for critically ill and intubated patients with lung infiltration. However, severe complications including tension pneumothorax and intrabronchial hemorrhage limit the application of needle biopsy. METHODS: A refined needle biopsy technique, named bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB), was performed on four intubated patients between August 2020 and April 2021. BUS-PTNB was done at bedside, following an EPUBNOW (evaluation, preparation, ultrasound location, bronchus blocking, needle biopsy, observation, and withdrawal of blocker) workflow. Parameters including procedure feasibility, sample acquisition, perioperative conditions, and complications were observed. Tissue specimens were sent to pathological examinations and microbial tests. RESULTS: Adequate specimens were successfully obtained from four patients. Diagnosis and treatment were correspondingly refined based on pathological and microbial tests. Intrabronchial hemorrhage occurred in patient 1 but was stopped by endobronchial blocker. Mild pneumothorax happened in patient 4 due to little air leakage, and closed thoracic drainage was placed. During the procedure, peripheral capillary hemoglobin oxygen saturation (SPO2), blood pressure, and heart rate of patient 4 fluctuated but recovered quickly. Vital signs were stable for patient 1-3. CONCLUSIONS: BUS-PTNB provides a promising, practical and feasible method in acquiring tissue specimen for critically ill patients under intratracheal intubation. It may facilitate the pathological diagnosis or other tissue-based tests for intubated patients and improve clinical outcomes.

Decreased mortality in acute respiratory distress syndrome patients treated with corticosteroids: an updated meta-analysis of randomized clinical trials with trial sequential analysis.

BACKGROUND: The possible benefits associated with corticosteroid treatment in acute respiratory distress syndrome (ARDS) patients are not fully known. We conducted an updated meta-analysis to assess the effect of corticosteroids in the treatment of patients with ARDS. METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library from inception to January 2021 via Ovid to identify randomized controlled trials evaluating the efficacy of glucocorticoids in the treatment of patients with ARDS. The primary outcome was hospital mortality. Secondary outcomes included the number of ventilator-free days at day 28, oxygenation improvement (PaO2/FIO2 ratios), and adverse events. RESULTS: Nine studies with 1371 participants were analyzed. The pooled analysis revealed that glucocorticoid use was associated with reduced mortality [relative risk (RR), 0.83; 95% confidence interval (CI) 0.74-0.93; P < 0.01; I2 = 37], and the statistical power was confirmed by trial sequential analysis. Glucocorticoids might also significantly increase the number of ventilator-free days at day 28 (mean deviation 3.66 days, 95% CI 2.64-4.68; P < 0.01) and improve oxygenation (standardized mean difference 4.17; 95% CI 2.32-6.02; P < 0.01). In addition, glucocorticoid use was not associated with increased risks of new infection (RR 0.84; 95% CI 0.70-1.01; P = 0.07) and hyperglycemia (RR 1.11; 95% CI 0.99-1.23; P = 0.06). CONCLUSIONS: The use of glucocorticoids might result in reduced mortality in patients with ARDS. Glucocorticoids might be recommended as an adjunct to standard care for ARDS; however, the optimal dose and duration of steroid therapy remains unknown and further studies are needed.

Multidetector computed tomography angiography prior to bronchial artery embolization helps detect culprit ectopic bronchial arteries and non-bronchial systemic arteries originating from subclavian and internal mammary arteries and improve hemoptysis-free early survival rate in patients with hemoptysis.

OBJECTIVES: To compare the average number of culprit arteries per patient, clinical success rate, and hemoptysis-free survival rate between hemoptysis patients with multidetector computed tomography (MDCT) angiography prior to bronchial artery embolization (BAE) and those without preprocedural MDCT angiography METHODS: This retrospective study was approved by the institutional review board with waiver of patient informed consent. From September 2012 to March 2017, 157 consecutive hemoptysis patients had been undergoing BAE. Among them, 106 patients received preprocedural MDCT angiography (MDCT group), while 51 patients did not receive preprocedural MDCT angiography (control group). The average number of culprit arteries per patient, clinical success rate, and hemoptysis-free survival rate were compared between the two groups. RESULTS: The average number of culprit ectopic bronchial arteries and that of non-bronchial systemic arteries originating from the subclavian and internal mammary arteries per patient in the MDCT group were both significantly higher than those in the control group (0.15 ± 0.51 vs 0.04 ± 0.20, p = 0.022, and 0.17 ± 0.56 vs 0.08 ± 0.39, p = 0.040, respectively). The clinical success rate of BAE with preprocedural MDCT angiography tended to be higher than that without MDCT angiography (97.2 vs 88.2%, p = 0.057). Importantly, patients in the MDCT group had a significantly higher hemoptysis-free early survival rate compared to those in the control group (96.1 vs 86.7%, p = 0.031). CONCLUSIONS: Preprocedural MDCT angiography helps detect culprit ectopic bronchial arteries and non-bronchial systemic arteries originating from subclavian and internal mammary arteries during BAE, and can improve the hemoptysis-free early survival rate, which could be recommended as a regular examination prior to BAE in patients with hemoptysis. KEY POINTS: • Preprocedural MDCT angiography helps detect culprit ectopic bronchial arteries and NBSAs originating from subclavian and internal mammary arteries during BAE. • Conducting MDCT angiography prior to BAE can improve hemoptysis-free early survival rate in hemoptysis patients.

Nucleic Acid Amplification Testing and Sequencing Combined with Acid-Fast Staining in Needle Biopsy Lung Tissues for the Diagnosis of Smear-Negative Pulmonary Tuberculosis.

BACKGROUND: Smear-negative pulmonary tuberculosis (PTB) is common and difficult to diagnose. In this study, we investigated the diagnostic value of nucleic acid amplification testing and sequencing combined with acid-fast bacteria (AFB) staining of needle biopsy lung tissues for patients with suspected smear-negative PTB. METHODS: Patients with suspected smear-negative PTB who underwent percutaneous transthoracic needle biopsy between May 1, 2012, and June 30, 2015, were enrolled in this retrospective study. Patients with AFB in sputum smears were excluded. All lung biopsy specimens were fixed in formalin, embedded in paraffin, and subjected to acid-fast staining and tuberculous polymerase chain reaction (TB-PCR). For patients with positive AFB and negative TB-PCR results in lung tissues, probe assays and 16S rRNA sequencing were used for identification of nontuberculous mycobacteria (NTM). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of PCR and AFB staining were calculated separately and in combination. RESULTS: Among the 220 eligible patients, 133 were diagnosed with TB (men/women: 76/57; age range: 17-80 years, confirmed TB: 9, probable TB: 124). Forty-eight patients who were diagnosed with other specific diseases were assigned as negative controls, and 39 patients with indeterminate final diagnosis were excluded from statistical analysis. The sensitivity, specificity, PPV, NPV, and accuracy of histological AFB (HAFB) for the diagnosis of smear-negative were 61.7% (82/133), 100% (48/48), 100% (82/82), 48.5% (48/181), and 71.8% (130/181), respectively. The sensitivity, specificity, PPV, and NPV of histological PCR were 89.5% (119/133), 95.8% (46/48), 98.3% (119/121), and 76.7% (46/60), respectively, demonstrating that histological PCR had significantly higher accuracy (91.2% [165/181]) than histological acid-fast staining (71.8% [130/181]), P < 0.001. Parallel testing of histological AFB staining and PCR showed the sensitivity, specificity, PPV, NPV, and accuracy to be 94.0% (125/133), 95.8% (46/48), 98.4% (125/127), 85.2% (46/54), and 94.5% (171/181), respectively. Among patients with positive AFB and negative PCR results in lung tissue specimens, two were diagnosed with NTM infections (Mycobacterium avium-intracellulare complex and Mycobacterium kansasii). CONCLUSION: Nucleic acid amplification testing combined with acid-fast staining in lung biopsy tissues can lead to early and accurate diagnosis in patients with smear-negative pulmonary tuberculosis. For patients with positive histological AFB and negative tuberculous PCR results in lung tissue, NTM infection should be suspected and could be identified by specific probe assays or 16S rRNA sequencing.

Air Cushion Convection Inhibiting Icing of Self-Cleaning Surfaces.

Anti-icing surfaces/interfaces are of considerable importance in various engineering fields under natural freezing environment. Although superhydrophobic self-cleaning surfaces show good anti-icing potentials, promotion of these surfaces in engineering applications seems to enter a "bottleneck" stage. One of the key issues is the intrinsic relationship between superhydrophobicity and icephobicity is unclear, and the dynamic action mechanism of "air cushion" (a key internal factor for superhydrophobicity) on icing suppression was largely ignored. Here we report that icing inhibition (i.e., icing-delay) of self-cleaning surfaces is mainly ascribed to air cushion and its convection. We experimentally found air cushion on the porous self-cleaning coating under vacuum environments and on the water/ice-coating interface at low temperatures. The icing-delay performances of porous self-cleaning surfaces compared with bare substrate, up to 10-40 min under 0 to ∼-4 °C environments close to freezing rain, have been accurately real-time recorded by a novel synergy method including high-speed photography and strain sensing voltage. Based on the experimental results, we innovatively propose a physical model of "air cushion convection inhibiting icing", which envisages both the static action of trapped air pocket without air flow and dynamic action of air cushion convection. Gibbs free energy of water droplets increased with the entropy of air derived from heat and mass transfer between warmer air underneath water droplets and colder surrounding air, resulting in remarkable ice nucleation delay. Only when air cushion convection disappears can ice nucleation be triggered on suitable Gibbs free energy conditions. The fundamental understanding of air cushion on anti-icing is an important step toward designing optimal anti-icing surfaces for practical engineering application.

CT-guided percutaneous transthoracic needle biopsy for paramediastinal and nonparamediastinal lung lesions: Diagnostic yield and complications in 1484 patients.

Computed tomography-guided percutaneous transthoracic needle biopsy (PTNB) is used for identifying paramediastinal lung lesions that cannot be diagnosed by bronchoscopy, but the diagnostic performance and complication rate are unreported.This retrospective study was approved by the institutional review board committee. A total of 1484 patients who underwent PTNB between April 2012 and April 2015 were enrolled. The cohort was divided into a paramediastinal (n = 195) and a nonparamediastinal group (n = 1289) based on lesion location. Diagnostic yield for malignancy and complication rates were analyzed in both groups. Univariate and multivariate logistic regression analysis was used to determine independent risk factors for hemoptysis complication in the paramediastinal group.Percutaneous transthoracic needle biopsy showed 95.6% (109/114) sensitivity and 100% (77/77) specificity for the diagnosis of lesions in the paramediastinal group, with similar accuracy (95.4%, 186/195) to that in the nonparamediastinal group (94.7%, 1221/1289; P = 0.699). Compared with PTNB for nonparamediastinal lesions, PTNB for paramediastinal lesions demonstrated a comparable pneumothorax rate (8.21% vs 8.69%; P = 0.823) and hemothorax rate (2.56% vs 1.47%; P = 0.261), and a higher hemoptysis rate (28.2% vs 19.4%; P = 0.005). Among 6 defined paramediastinal regions, the overall complication rate was the highest in the posterior region (42.4%) and the lowest in the paraventricular region (13.6%). Multivariate analysis revealed that lesion size of 2 to 3 cm (odds ratio [OR] 3.22), intrapulmonary length of needle path >2 cm (OR 8.85), and proximal to pulmonary artery (OR 10.33) were independent risk factors for hemoptysis in the paramediastinal group.Computed tomography-guided PTNB can diagnose paramediastinal lesions with high yield and acceptable complication rates. Given higher rate of hemoptysis in PTNB for paramediastinal lesions, more attention should be paid in cases with high risks.

Efficacy of two noninvasive weaning strategies in intubated patients with chronic obstructive pulmonary disease: A meta-analysis and indirect treatment comparison.

The purpose of our indirect comparison was to explore the optimal switching time to noninvasive ventilation for further weaning in patients with chronic obstructive pulmonary disease (COPD) undergoing invasive mechanical ventilation. A comprehensive literature search was performed to identify randomized controlled trials comparing noninvasive weaning at spontaneous breathing trial (SBT) failure after meeting simple weaning criteria or at the pulmonary infection control window (PIC window) with conventional invasive weaning in COPD patients. Using conventional invasive weaning as a bridge, we indirectly compared the two noninvasive weaning strategies using the Bucher approach. Noninvasive weaning at SBT failure after meeting simple weaning criteria was associated with an extended duration of endotracheal mechanical ventilation (standardized mean difference 1.90, 95% CI 1.27-2.53, P < 0.001) compared with noninvasive weaning at the PIC window. No significant differences in mortality or the rate of ventilator-associated pneumonia were observed. Our study suggests that the PIC window may be a promising switching time for noninvasive weaning in COPD patients.

A Novel Combination of Calprotectin and CXCL12 for Predicting Malignancy in Patients with Exudative Pleural Effusion.

Pleural effusion (PE) remains a significant challenge and public health problem, which needs novel noninvasive biomarkers for the precise diagnosis. The aim of this study was to further determine the clinical efficacy and diagnostic accuracy of a novel combination of calprotectin and CXCL12 for predicting malignancy in patients with exudative PE.Calprotectin and CXCL12 concentrations were measured in 95 individuals of exudative PE, with 39 malignant PE (MPE) and 56 benign PE (BPE). The accuracy of calprotectin and CXCL12 levels for discriminating MPE from BPE or tuberculous PE were evaluated using receiver-operating characteristic (ROC) curves. Univariate and multivariate logistic regression analyses were performed to test the association between calprotectin and CXCL12 levels and MPE.Calprotectin and CXCL12 levels of patients with MPE were significantly lower than that of BPE and tuberculous PE (P < 0.05). The area under the curve (AUC) of calprotectin and CXCL12 was 0.683 and 0.641 in MPE and BPE, and a combination of calprotectin ≤500.19 ng/mL and CXCL12 ≤6.11 ng/mL rendered a sensitivity and specificity of 48.72% and 78.57%, respectively. While in MPE and tuberculous PE, the AUC of calprotectin and CXCL12 was 0.696 and 0.690, and a combination of calprotectin ≤421.73 ng/mL and CXCL12 ≤3.71 ng/mL presented a sensitivity and specificity of 25.64% and 95.45%, respectively. Multivariate logistic regression demonstrated that both calprotectin and CXCL12 were independent predictors of MPE.Calprotectin and CXCL12 in pleural fluid are informative diagnostic biomarkers for predicting patients with MPE.

Analysis of mutants from a genetic screening reveals the control of intestine and liver development by many common genes in zebrafish.

Both the intestine and liver develop from the endoderm, yet little is known how these two digestive organs share and differ in their developmental programs, at the molecular level. A classical forward genetic screen, with no gene bias, is an effective way to address this question by examining the defects of the intestine and liver in obtained mutants to assess mutated genes responsible for the development of either organ or both. We report here such a screen in zebrafish. ENU was used as the mutagen because of its high mutagenic efficiency and no site preference. Embryos were collected at 3.5 dpf for RNA whole mount in situ hybridization with a cocktail probe of the intestine marker ifabp and the liver marker lfabp to check phenotypes and determine their parental heterozygosis. A total of 52 F2 putative mutants were identified, and those with general developmental defects were aborted. To rule out non-inheritable phenotypes caused by high mutation background, F2 putative mutants were outcrossed with wild type fish and a re-screen in F3 generations was performed. After complementation tests between F3 mutants with similar phenotypes originating from the same F2 families, a total of 37 F3 mutant lines originated from 22 F2 families were identified after screening 78 mutagenized genomes. Classification of mutant phenotypes indicated that 31 out of the 37 mutants showed defects in both the intestine and liver. In addition, four "intestine specific mutants" and two "liver specific mutants" showed selectively more severe phenotype in the intestine and liver respectively. These results suggested that the intestine and liver share a substantial number of essential genes during both organs development in zebrafish. Further studies of the mutants are likely to shed more insights into the molecular basis of the digestive system development in the zebrafish and vertebrate.

Initial synchronized intermittent mandatory ventilation versus assist/control ventilation in treatment of moderate acute respiratory distress syndrome: a prospective randomized controlled trial.

BACKGROUND: Assist/control (A/C) ventilation may induce delirium in patients with acute respiratory distress syndrome (ARDS). We conducted a trial to determine whether initial synchronized intermittent mandatory ventilation with pressure support (SIMV + PS) could improve clinical outcomes in these patients. METHODS: Intubated patients with moderate ARDS were enrolled and we compared SIMV + PS with A/C. Identical sedation, analgesia and ventilation strategies were performed. The co-primary outcomes were early (≤72 h) partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) and incidence of delirium. The secondary outcomes were all-cause in-hospital mortality, dosages of analgesics and sedatives, incidence of patient-ventilator asynchrony, and duration of mechanical ventilation and hospital stay. RESULTS: We screened 2,684 patients and 40 patients were enrolled in our study. In SIMV + PS, early (≤72 h) PaO2/FiO2 was greater improved than that at baseline and that in A/C (P<0.05) with lower positive end-expiratory pressure (PEEP) (8.7±3.0 vs. 10.3±3.2, P<0.001) and FiO2 (58%±18% vs. 67%±19%, P<0.001). We found more SIMV + PS success (defined as SIMV + PS successfully applied without switching to A/C) (100.0% vs. 16.7%, P<0.001), less male (46.3% vs. 85.7%, P=0.015) and pulmonary etiology of ARDS (53.8% vs. 92.9%, P=0.015), and lower PEEP (9.1±3.1 vs. 10.3±3.3, P=0.004) and FiO2 (58%±19% vs. 71%±19%, P<0.001) in survival patients. However, there were no significant differences in incidence of delirium and mortality, dosages of analgesics and sedatives, incidence of patient-ventilator asynchrony, duration of mechanical ventilation and hospital stay (P>0.05). CONCLUSIONS: In patients with moderate ARDS, SIMV + PS can safely and effectively improve oxygenation, but does not decrease mortality, incidence of delirium and patient-ventilator asynchrony, dosages of analgesics and sedatives, and duration of mechanical ventilation and hospital stay.

Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: a systematic review.

BACKGROUND: To evaluate the safety and efficacy of using sildenafil for ≥ 12 weeks to treat pulmonary arterial hypertension (PAH). METHODS: Randomized controlled trials (RCTs) of sildenafil therapy in patients with PAH published through May 2013 were identified by searching PubMed, the Cochrane Library, Embase, relevant websites, and reference lists of relevant studies. Two reviewers independently assessed the quality of the trials and extracted information. RESULTS: Meta-analysis was carried out with subsets of 4 trials involving 545 patients. Sildenafil therapy significantly reduced clinical worsening of PAH compared to placebo (RR 0.39, 95% CI 0.21-0.69) and improved the 6-min walk distance (MD 31.3 m, 95% CI 18.01-44.67), WHO functional class, hemodynamic variables and health-related quality of life (HRQoL). Sildenafil did not, however, improve all-cause mortality (RR 0.29, 95% CI 0.02-4.94) or Borg dyspnea score relative to placebo, nor did it significantly affect the incidence of serious adverse events. In fact, sildenafil was associated with higher total incidence of adverse events, but these additional events were mild to moderate in severity and were tolerable. CONCLUSIONS: Sildenafil therapy lasting ≥ 12 weeks improves multiple clinical and hemodynamic outcomes in patients with PAH, but it appears to have no effect on mortality or serious adverse events. The long-term efficacy and safety of sildenafil therapy in PAH requires further study based on large and well-designed RCTs.

[¹²5I]AT-1012, a new high affinity radioligand for the α3ß4 nicotinic acetylcholine receptors.

Recent genetic and pharmacological studies have implicated the α3, ß4 and α5 subunits of the nicotinic acetylcholine receptor (nAChR) in dependence to nicotine and other abused drugs and nicotine withdrawal. The α3ß4* nAChR subtype has been shown to co-assemble with the α5 or ß3 nAChR subunits, and is found mainly in the autonomic ganglia and select brain regions. It has been difficult to study the α3ß4 nAChR because there have been no selective nonpeptidic ligands available to independently examine its pharmacology. We recently reported the synthesis of a [(125)I]-radiolabeled analog of a high affinity, selective small-molecule α3ß4 nAChR ligand, AT-1012. We report here the vitro characterization of this radioligand in receptor binding and in vitro autoradiographic studies targeting the α3ß4* nAChR. Binding of [(125)I]AT-1012 was characterized at the rat α3ß4 and α4ß2 nAChR transfected into HEK cells, as well as at the human α3ß4α5 nAChR in HEK cells. Binding affinity of [(125)I]AT-1012 at the rat α3ß4 nAChR was 1.4 nM, with a B(max) of 10.3 pmol/mg protein, similar to what was determined for unlabeled AT-1012 using [(3)H]epibatidine. Saturation isotherms suggested that [(125)I]AT-1012 binds to a single site on the α3ß4 nAChR. Similar high binding affinity was also observed for [(125)I]AT-1012 at the human α3ß4α5 nAChR transfected into HEK cells. [(125)I]AT-1012 did not bind with high affinity to membranes from α4ß2 nAChR-transfected HEK cells. Binding studies with [(3)H]epibatidine further confirmed that AT-1012 had over 100-fold binding selectivity for α3ß4 over α4ß2 nAChR. K(i) values determined for known nAChR compounds using [(125)I]AT-1012 as radioligand were comparable to those obtained with [(3)H]epibatidine. [(125)I]AT-1012 was also used to label α3ß4 nAChR in rat brain slices in vitro using autoradiography, which showed highly localized binding of the radioligand in brain regions consistent with the discreet localization of the α3ß4 nAChR. We demonstrate that [(125)I]AT-1012 is an excellent tool for labeling the α3ß4 nAChR in the presence of other nAChR subtypes.